FE65 and FE65L1 amyloid precursor protein‐binding protein compound null mice display adult‐onset cataract and muscle weakness

Abstract

FE65 and FE65L1 are cytoplasmic adaptor proteins that bind a variety of proteins, including the amyloid precursor protein, and that mediate the assembly of multimolecular complexes. We previously reported that FE65/FE65L1 double knockout (DKO) mice display disorganized laminin in meningeal fibroblasts and a cobblestone lissencephaly-like phenotype in the developing cortex. Here, we examined whether loss of FE65 and FE65L1 causes ocular and muscular deficits, 2 phenotypes that frequently accompany cobblestone lissencephaly. Eyes of FE65/FE65L1 DKO mice develop normally, but lens degeneration becomes apparent in young adult mice. Abnormal lens epithelial cell migration, widespread small vacuole formation, and increased laminin expression underneath lens capsules suggest impaired interaction between epithelial cells and capsular extracellular matrix in DKO lenses. Cortical cataracts develop in FE65L1 knockout (KO) mice aged 16 months or more but are absent in wild-type or FE65 KO mice. FE65 family KO mice show attenuated grip strength, and the nuclei of DKO muscle cells frequently locate in the middle of muscle fibers. These findings reveal that FE65 and FE65L1 are essential for the maintenance of lens transparency, and their loss produce phenotypes in brain, eye, and muscle that are comparable to the clinical features of congenital muscular dystrophies in humans.

FE65 and FE65L1 share common synaptic functions and genetically interact with the APP family in neuromuscular junction formation

“…We observed strong deficits for the FE65/FE65L1-DKO mice in the MWM tasks. Since interpretation of the cognitive deficits observed for these mice is confounded by altered anxiety, activity and possibly visual abilities 16 the analyzed data are not further discussed, but are presented in Supplementary Fig. S1 .…”

“…Yet, only FE65/FE65L1-DKO mice showed deficits in the maintenance phase of LTP and only FE65-KO mice showed a trend towards PTP deficits. A subset of aged FE65L1 KO mice (16–20 months old) demonstrated cataract and corneal ulcerations 16 . Thus, we cannot formally exclude the possibility that younger FE65L1 KO mice have some visual acuity deficit that interferes with their performance in the MWM tasks.…”

“…The second FE65 knockout mouse model, lacking both the p97 and p60 isoforms displays deficits in the hanging wire task that are also observed in FE65L1-KO mice 16 . In contrast to the FE65/FE65L1 double knockout (DKO) mice, which exhibit deficits in neuronal positioning and axon outgrowth in the developing cortex, there are no overt morphological abnormalities present in FE65-KO and FE65L1-KO mouse brains 14 .…”

APP Protein Family Signaling at the Synapse: Insights from Intracellular APP-Binding Proteins

“…In contrast, memory deficits were observed in the MWM test for the FE65 KO (lacking both p60 and p97 isoforms) and FE65L1 KO mice in our study (Strecker et al, 2016). Confounding behaviors for locomotion analyses and possible loss of vision in FE65/FE65L1 DKO mice (Suh et al, 2015; Strecker et al, 2016) made it impossible to interpret the MWM spatial learning deficits observed for FE65/FE65L1 DKO mice.…”

“…These are aggravated in FE65/FE65L1 DKO compared to FE65 or FE65L1 KO mice NMJs (Strecker et al, 2016), possibly leading to muscle degeneration/denervation (Suh et al, 2015) and the locomotion deficits and impairments in strength observed in these mice (Strecker et al, 2016). …”